Current research suggests that loss of the vasodilator, anti-thrombotic, and anti-inflammatory properties of the vascular endothelium plays a dynamic role in the pathogenesis of cardiovascular disease. Impaired endothelial function, including impaired nitric oxide-dependent vasodilation is associated with cardiovascular disease risk factors. Further, there is growing evidence that endothelial function can be improved by risk modification. However, the available studies have not definitively resolved the issue of the cross-sectional correlates of endothelial dysfunction because they have been limited to small samples of highly selected patients. For example, it remains unclear whether hypercholesterolemia, hypertension, or elevated glucose levels are independent determinants of endothelial dysfunction. Most importantly, no study has shown a relation between endothelial dysfunction and increased cardiovascular risk. Such a demonstration would increase our understanding of the pathogenesis of cardiovascular disease and aid clinicians in identifying high risk individuals who would benefit most from intervention. Completion of such a study will require assessment of endothelial function in a large, well-characterized population. Recently, a rapid, non-invasive method for assessment of endothelial function was developed using brachial artery ultrasound. Using this method, endothelial function will be examined in about 3,800 men and women of the Framingham Heart Study. The specific objects of this proposal are to: 1. Examine the cross-sectional correlates of endothelial function with known coronary risk factors, 2. Perform cross- sectional analyses on the relation of endothelial function to prevalent cardiovascular disease, 3. Observe the adjusted relation of endothelial function to incident and recurrent cardiovascular events. Our central hypothesis is that the presence of endothelial dysfunction is an independent risk factor for cardiovascular disease events. The Framingham Study is uniquely suited for this proposal by virtue of the single site population-based design, the broad age range of subjects, the availability of extensive antecedent and contemporary risk factor data, expertise in non-invasive imaging and quality control procedures, and the availability of long-term, longitudinal follow-up. The proposed study provides a unique opportunity to assess the prognostic importance of endothelial function and is likely to yield new information that will directly improve the prevention and management of cardiovascular disease.